1521-0081/73/2/792–827$35.00 https://doi.org/10.1124/pharmrev.120.000072 PHARMACOLOGICAL REVIEWS Pharmacol Rev 73:792–827, April 2021 Copyright © 2021 by The Author(s) This is an open access article distributed under the CC BY Attribution 4.0 International license. ASSOCIATE EDITOR: FINN OLAV LEVY Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics Peter Garred, Andrea J. Tenner, and Tom E. Mollnes Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark, and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (P.G.); Departments of Molecular Biology and Biochemistry, Neurobiology and Behavior, and Pathology and Laboratory Medicine, University of California, Irvine, California (A.J.T.); and Research Laboratory, Nordland Hospital, Bodø, Norway, Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway (T.E.M.); Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway (T.E.M.); and Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway (T.E.M.) Abstract ...................................................................................794 Significance Statement. ..................................................................794 I. Introduction . ..............................................................................794 A. An Overview of the Complement System ...............................................794 1. Discovery of the System. ............................................................794 Downloaded from 2. The History of Complement Research from the 1880s to 1980s .......................796 B. The Complement System Approach in the Clinic: The Therapeutic Era ..................796 1. The Revolution of Complement Research for the Last 3 Decades . ...................796 2. Complement from Bench to Bedside: Today’s Indications . .........................798 II. Complement Deficiencies and Loss- or Gain-of-Function Mutations. .........................798 A. Classical Pathway Deficiencies . ......................................................798 by guest on September 28, 2021 1. The Components of the Classical Pathway, Their Activation, and Regulation . .......798 2. Deficiencies of the Classical Pathway Components...................................799 3. Disturbances of the Classical Pathway and Therapeutic Targets . ...................799 B. Lectin Pathway Deficiencies ............................................................799 1. The Components of the Lectin Pathway, Their Activation, and Regulation ...........799 2. Deficiencies of the Lectin Pathway Components .....................................800 3. Disturbances of the Lectin Pathway and Therapeutic Targets........................802 C. Alternative Pathway Deficiencies . ......................................................802 1. The Components of the Alternative Pathway, Their Activation, and Regulation ......802 2. Deficiencies of the Alternative Pathway Components . ...............................802 3. Disturbances of the Alternative Pathway and Therapeutic Targets ...................803 D. Terminal Pathway Deficiencies . ......................................................804 1. The Components of the Terminal Pathway, Their Activation, and Regulation. .......804 2. Deficiencies of the Terminal Pathway Components . ...............................804 3. Disturbances of the Terminal Pathway and Therapeutic Targets . ...................805 E. Therapeutic Approach to Treat Complement Deficiencies or to Enhance Its Efficacy .....805 1. Substitution of Purified Components and Plasma ....................................805 2. Prophylactic and Symptomatic Treatment . ..........................................805 3. Liver Transplantation. ............................................................805 4. Triggering of Complement Activation in Individuals with a Normal Complement System: An Anticancer Approach....................................................805 5. Gene Therapy ......................................................................806 III. Role of Complement in Disease Pathophysiology. ..........................................806 Address correspondence to: Tom E. Mollnes, Research Laboratory, Nordland Hospital, N-8092 Bodø, Norway. E-mail: t.e.mollnes@ gmail.com A.J.T. received funding from National Institutes of Heath (NIH) National Institute on Aging [Grants R01AG060148 and R21AG061746]. Conflict of Interest: T.E.M. is a member of the Scientific Advisory Board of Ra Pharma/UCB. A.J.T. is a consultant for Montis. https://doi.org/10.1124/pharmrev.120.000072. 792 Pharmacological Targeting the Complement System 793 A. Consequences of a Dysfunctional Complement System . ...............................806 1. Decreased Regulatory Activity and Increased Activation Potential ...................806 2. Pathophysiologic Role of an Uncontrolled Overactivated System . ...................806 3. Complement Attack on Host Cells when They Lack Regulators . ...................807 4. Complement Attack in Tissue Damage and Common Pathophysiological Mecha- nisms to Treat a Broad Panel of Diseases . ..........................................808 IV. Therapeutic Complement Inhibition . ......................................................809 A. Diseases with a Potential for Complement Therapeutic Modulation . ...................809 1. Introduction: The Search for Complement as Pathophysiologic Mediator .............809 2. Neurologic Diseases.................................................................809 3. Eye Diseases .......................................................................810 4. Kidney Diseases . ..................................................................811 5. Hematologic Diseases . ............................................................812 6. Autoimmune Diseases . ............................................................813 7. Transplantation . ..................................................................813 8. Systemic Inflammation: Trauma Sepsis and the Pandemic Coronavirus Disease 2019. ..............................................................................814 V. Mode of Complement Inhibition ............................................................815 A. Targets to Be Inhibited ................................................................815 1. Introduction ........................................................................815 2. Classical and Lectin Pathway . ......................................................815 3. C3 and the Alternative Pathway ....................................................815 4. Terminal Pathway ..................................................................815 B. Reagents to Be Used . ..................................................................816 1. Monoclonal Antibodies and Their Derivatives. .....................................816 2. Small Molecular Peptides and Peptidomimetics. .....................................816 3. Aptamers . ........................................................................817 4. Recombinant Proteins and Conjugates...............................................817 C. Routes of Distribution..................................................................817 1. Locally .............................................................................817 2. Intravenously.......................................................................818 3. Orally ..............................................................................818 VI. Assays for Diagnostics and for Treatment Follow-up . .....................................818 A. Principles of Complement Assays. ......................................................818 1. Detection of Complement Activation. ................................................818 2. Screening for Total Complement Activity . ..........................................818 VII. Consequences of Therapeutic Complement Inhibition . .....................................819 A. Safety and Adverse Effects . ............................................................819 1. Safety and Adverse Effects of Established C5 Inhibition .............................819 2. Potential Adverse Effects of New Inhibitors .........................................820 B. Efficacy of Treatment ..................................................................820 1. Fully Complement-Dependent Diseases . ..........................................820 2. Diseases with Complex Pathophysiology. ..........................................820 VIII. Conclusions and Future Perspectives . ......................................................820 References . ..............................................................................820 ABBREVIATIONS: AAV, anti-neutrophilic cytoplasmic antibodies–associated vasculitis; aHUS, atypical HUS; AMD, age-related macula degeneration; APS, antiphospholipid syndrome; CAPS, catastrophic APS; C3aR, C3a receptor; C5aR1, C5a receptor 1; C5aR2, C5a receptor 2; C4BP, C4b-binding protein; C3G, C3 glomerulopathy; C3GN, C3 glomerulonephritis; CL, collectin; CNS, central nervous system; COVID-19, coronavirus disease 2019; CR, complement receptor; CRP, C-reactive protein; DAF, decay-accelerating factor; DAMP, damage-associated molecular pattern; DDD, dense deposit disease; Fc, fragment crystallizable; FDA, Food and Drug Administration; Gd-IgA1, galactose-deficient IgA1; GPI, glycosyl